PROJECT SUMMARY: The lack of a clear understanding of Disorders of Deglutition (DD) in infants, i.e., impair- ments in eating, dysfunctional swallowing, and aerodigestive symptoms contributes to the rising prevalence and consequences of dehydration, malnutrition, high tube-feeding rates, neurodevelopmental deficits, and chronic hospital visits. These problems are common in the neonatal intensive care units (NICUs) graduates, particularly among those born prematurely or surviving after perinatal neuropathology. The estimated cost per neuropathol- ogy survivor varies from 350K to 500K US$, and prematurity contributes to a staggering, underestimated health care burden of over ~26 billion US$. This proposal addresses this knowledge deficit and sets the stage for early and safe-feeding intervention protocols in infants with DD by addressing both diagnostic- and rehabilitative-chal- lenges to alleviate infant eating concerns that are vital to improving aerodigestive health and neurodevelopment, which is our long-term goal. The central hypothesis is that characteristics of pharyngeal-, upper esophageal sphincter-, and esophageal-motility reflexes, and their contiguous and cross-systems relationships will differ in control and study infants. Our rationale is that identifying these sensory-motor biomarkers will clarify the specific pathophysiological changes contributing to DD in infants with neuropathology, so that inducible self-regulatory functions and recovery strategies can be developed. To accomplish this, novel, high-fidelity, video-integrated, high-resolution impedance manometry methods will be employed at the crib-side while monitoring physiological safety parameters in infants with DD but without neuropathology (control infants) and infants with DD and neu- ropathology (study infants). Our two specific aims are 1) to identify diagnostic biomarkers related to pharyngo- esophageal motility and airway safety which distinguish baseline and active swallowing mechanisms in control vs. study infants, and 2) to test the safety and effectiveness of targeted lingual nutritive stimulation in restoring pharyngo-esophageal motility and airway safety functions in tube-fed control and study infants during maturation. Applying robust state-of-the-art technological advances using video-integrated, high-resolution impedance ma- nometry at the crib-side, new mechanistic insights will be gained by examining the effects of targeted provocation on full column esophageal motility, and airway-digestive interactions. Completion of the proposed aims will 1) ad- vance data analysis algorithms and feeding protocols to facilitate transdisciplinary training, bio-feedback, and parent education; and 2) design a decision-making process to improve personalized nutritive therapies. This proposal addresses a critical need in neonatal gastroenterology by examining unique mechanisms and defining the basis for preventative and corrective therapies critical to addressing this challenging public health burden, which contributes to significant socio-economic burden, prolonged hospital stays, neurodevelopmental delays, or death. This will be accomplished by improving infant feeding, swallowing, airway, and digestive difficulties and advancing nutrition, growth, and long-term neurodevelopment, all within NIDDK's mission.